NM_022370.4:c.1331-49C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022370.4(ROBO3):c.1331-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,441,680 control chromosomes in the GnomAD database, including 228,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26556 hom., cov: 32)

Exomes 𝑓: 0.55 ( 201853 hom. )

Consequence

ROBO3
NM_022370.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.103

Publications

10 publications found

Variant links:

Genes affected

ROBO3 (HGNC:13433): (roundabout guidance receptor 3) This gene is a member of the Roundabout (ROBO) gene family that controls neurite outgrowth, growth cone guidance, and axon fasciculation. ROBO proteins are a subfamily of the immunoglobulin transmembrane receptor superfamily. SLIT proteins 1-3, a family of secreted chemorepellants, are ligands for ROBO proteins and SLIT/ROBO interactions regulate myogenesis, leukocyte migration, kidney morphogenesis, angiogenesis, and vasculogenesis in addition to neurogenesis. This gene, ROBO3, has a putative extracellular domain with five immunoglobulin (Ig)-like loops and three fibronectin (Fn) type III motifs, a transmembrane segment, and a cytoplasmic tail with three conserved signaling motifs: CC0, CC2, and CC3 (CC for conserved cytoplasmic). Unlike other ROBO family members, ROBO3 lacks motif CC1. The ROBO3 gene regulates axonal navigation at the ventral midline of the neural tube. In mouse, loss of Robo3 results in a complete failure of commissural axons to cross the midline throughout the spinal cord and the hindbrain. Mutations ROBO3 result in horizontal gaze palsy with progressive scoliosis (HGPPS); an autosomal recessive disorder characterized by congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to cross the midline in the medulla. [provided by RefSeq, May 2019]

ROBO3 Gene-Disease associations (from GenCC):

gaze palsy, familial horizontal, with progressive scoliosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp

ROBO3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 11-124872835-C-T is Benign according to our data. Variant chr11-124872835-C-T is described in ClinVar as Benign. ClinVar VariationId is 1327965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO3	NM_022370.4 link	c.1331-49C>T		intron_variant	Intron 8 of 27	ENST00000397801.6	NP_071765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6 link	c.1331-49C>T		intron_variant	Intron 8 of 27	1	NM_022370.4	ENSP00000380903.1
ROBO3	ENST00000538940.5 link	c.1265-49C>T		intron_variant	Intron 7 of 26	5		ENSP00000441797.1

Frequencies

GnomAD3 genomes

AF:

0.576

AC:

87455

AN:

151878

Hom.:

26540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.716

Gnomad AMI

AF:

0.549

Gnomad AMR

AF:

0.420

Gnomad ASJ

AF:

0.590

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.391

Gnomad FIN

AF:

0.608

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.569

Gnomad OTH

AF:

0.564

GnomAD2 exomes

AF:

0.491

AC:

55080

AN:

112096

AF XY:

0.490

show subpopulations

Gnomad AFR exome

AF:

0.734

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.574

Gnomad EAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.602

Gnomad NFE exome

AF:

0.582

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.551

AC:

710705

AN:

1289684

Hom.:

201853

Cov.:

AF XY:

0.547

AC XY:

345755

AN XY:

631700

show subpopulations

African (AFR)

AF:

0.724

AC:

20889

AN:

28862

American (AMR)

AF:

0.331

AC:

8687

AN:

26228

Ashkenazi Jewish (ASJ)

AF:

0.573

AC:

11318

AN:

19762

East Asian (EAS)

AF:

0.144

AC:

5139

AN:

35666

South Asian (SAS)

AF:

0.390

AC:

25827

AN:

66306

European-Finnish (FIN)

AF:

0.598

AC:

27608

AN:

46132

Middle Eastern (MID)

AF:

0.542

AC:

1951

AN:

3598

European-Non Finnish (NFE)

AF:

0.575

AC:

580397

AN:

1009540

Other (OTH)

AF:

0.539

AC:

28889

AN:

53590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

15462

30924

46386

61848

77310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16318

32636

48954

65272

81590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.576

AC:

87504

AN:

151996

Hom.:

26556

Cov.:

AF XY:

0.568

AC XY:

42205

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.716

AC:

29681

AN:

41462

American (AMR)

AF:

0.419

AC:

6407

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.590

AC:

2047

AN:

3472

East Asian (EAS)

AF:

0.116

AC:

598

AN:

5158

South Asian (SAS)

AF:

0.389

AC:

1876

AN:

4818

European-Finnish (FIN)

AF:

0.608

AC:

6416

AN:

10552

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.569

AC:

38633

AN:

67932

Other (OTH)

AF:

0.557

AC:

1175

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1854

3707

5561

7414

9268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.559

Hom.:

33213

Bravo

AF:

0.568

Asia WGS

AF:

0.288

AC:

1002

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis 1

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.4

(source)

DANN

Benign

0.49

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over